Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues to focus on mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neuronal functions. Our main interest is the function of the dorsal striatum (DS), a brain region involved in action control and selection, as well as action learning. Opiates/Opiate Receptor-Mediated Long-Term Depression at Striatal Synapses. We have continued our studies of long-term synaptic depression (LTD) at synapses in striatum. Previous work in the laboratory indicated that different presynaptic G-protein-coupled receptors (GPCRs) can initiate long-lasting depression of glutamate release at synapses onto striatal medium spiny neurons (MSNs). The main property shared by these receptors is activation of Gi/o-type G proteins. Opioid peptides, such as enkephalin and dynorphin, are endogenous agonists for the opiate receptors. The three classic opiate receptors are the Gi/o-coupled mu, delta and kappa subtypes (MORs, DORS and KORs respectively). These receptors are present in striatum, including on presynaptic elements in this brain region. The opiate peptides enkephalin and dynorphin are also abundant in striatum, where their expression is segregated in two different MSN-subtypes known as the direct and indirect pathways MSNs, respectively. The opiate peptides and their cognate receptors are implicated in neural mechanisms of reward, and we were thus interested in determining how they affect synaptic transmission in the striatum, as this brain region has roles in reward-related behaviors. When recording from MSNs in brain slices from mouse or rat, we have observed that activation of any of the three ORs produces inhibition of glutamatergic synaptic transmission. Antagonists of the different receptors counteract the effects of subtype-selective agonists, and thus the different ORs appear to act independently to depress transmission. Our findings indicate that synaptic depression is mainly due to decreased neurotransmitter release. Surprisingly, the OR agonist-induced depression is long-lasting, persisting for up to 30 min even when agonist application has been terminated. Using blockers of specific peptidases that are known to degrade enkephalin and dynorphin reveals long-lasting synaptic depression that is OR-mediated, indicating that the endogenous neuropeptides can activate these responses. Opiate agonists are used therapeutically for pain treatment, and thus it is important to know if in vivo exposure to such drugs alters opiate-mediated striatal LTD. Indeed, opiate LTD is not inducible in striatal slices made from animals within 24 hr of a single in vivo injection of oxycodone, a widely-used opiate analgesic. Our findings to date indicate that endogenous opiates produce a form of LTD at glutamatergic striatal synapses that has properties similar to that produced by other neurotransmitters that activate Gi/o-coupled GPCRs. Furthermore, this synaptic plasticity may be prevented or occluded during therapeutic treatment with OR agonists, and could also play roles in habitual drug use and the development of opiate addiction. Ethanol actions at striatal GABAergic synapses We are also continuing our studies of ethanol (EtOH) effects on GABAergic synaptic transmission in dorsolateral (DLS) and dorsomedial striatum (DMS). Our observation that EtOH inhibits GABAergic synaptic transmission in DLS MSNs via a presynaptic mechanism, while potentiating transmission in DMS, suggests differential mechanisms of EtOH action in the two striatal subregions. We have begun using optogenetic techniques to determine if these differential EtOH effects occur at different afferent inputs to MSNs. The two predominant GABAergic inputs to striatal MSNs come from axon collaterals of other MSNs that synapse mainly on the MSN dendrites, and from the fast-spiking interneurons that synapse mainly near the MSN soma. We can activate the two GABAergic inputs independently by expressing channel rhodopsin 2 selectively in the two neuronal subtypes and activating this channel with light. Using this approach, we find that EtOH inhibits GABAergic input to MSNs from both neuronal subtypes in the DLS. We are now beginning to use the same approach in the DMS. The opposing effects in DLS and DMS are surprising, and may indicate that EtOH suppresses the output of the DMS that is important for goal-directed actions, while enhancing the output of DLS which is involved in habit formation.